Decitabine and Cedazuridine

Use in patients with hepatic impairment has not been established. Caution must be exercised in the administration of medicinal product to patients with hepatic impairment and in patients who develop signs or symptoms of hepatic impairment. Liver function tests must be performed prior to the initiation of therapy, prior to each treatment cycle, and as clinically indicated.

Due to the potential for increased adverse reactions, patients with moderate renal impairment (CrCl 30 to 59 mL/min/1.73 m²) must be monitored.

Use in patients with severe renal impairment has not been studied. Caution must be exercised in the administration of the medicinal product to patients with severe renal impairment (CrCl <30 mL/min). Renal function tests must be performed prior to the initiation of therapy, prior to each treatment cycle, and as clinically indicated.

No human data on the effect of decitabine and cedazuridine on fertility are available. Ovarian and testicular toxicity, including mutagenicity, has been observed in repeat-dose toxicity studies in mice. Because of the possibility of infertility as a consequence of therapy, men should seek advice on conservation of sperm and female patients of childbearing potential should seek consultation regarding oocyte cryopreservation prior to initiating treatment. Before starting treatment or planning pregnancy, consider the above guidance.

Cedazuridine is an inhibitor of CDA and thereby increases the exposure of decitabine following oral administration. Concomitant administration of decitabine/cedazuridine with medicinal products metabolised by CDA (i.e., cytarabine, gemcitabine, azacitidine) may result in increased systemic exposure with a potential for increased toxicity of these medicinal products. Co-administration of decitabine/cedazuridine with medicinal products metabolised primarily by CDA should be avoided.

Overall decitabine exposure has been shown to be reduced when decitabine is administered with a highfat, high-calorie meal.

Because decitabine is a substrate for the cytidine deaminase (CDA) enzyme, which metabolises decitabine resulting in an inactive deaminated form, other medicinal products inhibiting CDA should be avoided, as co-administration may result in increased decitabine exposure.

There are no or a limited amount of human data from the use of decitabine and cedazuridine in pregnant women.

Based on the results of embryo-foetal toxicity studies conducted in animals, decitabine/cedazuridine combination may harm the foetus when administered to pregnant women.

Studies in animals have shown reproductive toxicity.

Decitabine/cedazuridine combinaiton is not recommended during pregnancy and in women of childbearing potential not using effective contraception. A pregnancy test should be performed on all women of childbearing potential before treatment is started. If decitabine/cedazuridine is used during pregnancy, or if a patient becomes pregnant while receiving this medicinal product, the patient should be apprised of the potential hazard to the foetus.

It is unknown whether decitabine, cedazuridine, or their metabolites are excreted in breast milk.

A risk to the newborns/infants cannot be excluded.

Decitabine/cedazuridine combination is contraindicated during breast-feeding.

Women of childbearing potential/Contraception in men and women

Due to the genotoxic potential of decitabine, women of childbearing potential must use effective contraceptive measures and avoid becoming pregnant while being treated with decitabine/cedazuridine and for 6 months following completion of treatment. Men should use effective contraceptive measures and be advised to not father a child while receiving decitabine/cedazuridine, and for 3 months following completion of treatment.

The use of decitabine and cedazuridine with hormonal contraceptives has not been studied.

Fertility

No human data on the effect of decitabine and cedazuridine on fertility are available. Ovarian and testicular toxicity, including mutagenicity, has been observed in repeat-dose toxicity studies in mice. Because of the possibility of infertility as a consequence of therapy, men should seek advice on conservation of sperm and female patients of childbearing potential should seek consultation regarding oocyte cryopreservation prior to initiating treatment. Before starting treatment or planning pregnancy, consider the above guidance.

Decitabine/cedazuridine combination has moderate influence on the ability to drive and use machines. Patients should be advised that they may experience undesirable effects, such as anaemia during treatment. Therefore, caution should be observed when driving a car or operating machinery.

Summary of safety profile

The safety of decitabine/cedazuridine combination was evaluated in one Phase 3 study (ASTX727-02-EU) where 80 AML patients received the medicinal product. The overall safety profile for decitabine/cedazuridine is described below and also reflects the known safety profile of intravenous decitabine.

Among the 80 patients who received treatment, the most common adverse drug reaction (≥20%) including Grade ≥ 3 was thrombocytopaenia.

The most common serious adverse reactions (≥20%) were febrile neutropaenia and pneumonia.

Deaths while on treatment occurred in 24% of patients. The most frequent adverse reactions resulting in death included pneumonia (8%), sepsis (3%) and central nervous system haemorrhage in the setting of thrombocytopaenia (3%).

Permanent discontinuation occurred in 14% of patients while on treatment. The most frequent adverse reaction resulting in permanent discontinuation was pneumonia (5%).

Treatment interruption and dose reductions occurred in 48% of patients. The most frequent adverse reaction resulting in treatment interruption and dose reduction was myelosuppression occurring in 19% of patients (n=15) (neutropaenia [13%, n=10], febrile neutropaenia [5%, n=4], and thrombocytopaenia [3%, n=2]). The adverse reaction pneumonia led to treatment interruption and dose reduction in 5% of patients.

Tabulated list of adverse reactions

The safety evaluation of adverse reactions is largely based on experience with Dacogen in patients with AML. The safety of decitabine/cedazuridine in adult patients was evaluated in a safety population that included AML patients from one Phase 3 study (ASTX727-02-EU, N=80).

Among the 80 patients who received decitabine/cedazuridine, 38% were exposed for 6 months or longer and 6% were exposed for greater than 1 year.

The table below lists adverse drug reactions associated with decitabine/cedazuridine (N=80), or that have been associated with intravenous decitabine, according to system organ class (SOC) in MedDRA. Within each SOC, the adverse drug reactions are ranked by frequency and then presented in order of decreasing seriousness. The corresponding frequency category for each adverse drug reaction is defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1 000 to <1/100); rare (≥1/10 000 to <1/1 000); very rare (<1/10 000); not known (cannot be estimated from available data).

Adverse drug reactions observed with decitabine/cedazuridine combination or with intravenous decitabine therapy in AML patients:

^a The corresponding frequency category for each adverse drug reaction is based on the CIOMS III convention
^b Grouped terms include anal abscess, anorectal infection, bacteraemia, cellulitis, cellulitis staphylococcal, corona virus infection, coronavirus test positive, enterococcal bacteraemia, enterocolitis viral, erythema, escherichia bacteraemia, folliculitis, furuncle, gingival swelling, herpes virus infection, infection, klebsiella bacteraemia, nasal congestion, nasopharyngitis, oral candidiasis, oral herpes, oropharyngeal candidiasis, otitis externa, periodontitis, pharyngitis, polyserositis, pseudomonal bacteraemia, staphylococcal bacteraemia, staphylococcal infection, streptococcal bacteraemia, respiratory tract infection, skin infection, tooth abscess, tooth infection, upper respiratory tract infection, varicella zoster virus infection
^c Grouped terms include bronchitis, pneumonia
^d Grouped terms include sepsis, septic shock, systemic candidiasis, urosepsis
^e Grouped terms include bacteriuria, cystitis, dysuria, escherichia urinary tract infection, urinary tract infection, urinary tract infection enterococcal
^f Grouped terms include sinusitis aspergillus, sinusitis fungal
^g Sinusitis bacterial was not observed in the clinical trial with decitabine/cedazuridine, however sinusitis (organism not specified) was observed in clinical trials with IV decitabine at a frequency of common (3%, 1%)
^h Based on laboratory values
ⁱ Thrombocytopaenia may lead to bleeding and haemorrhagic reactions that may be fatal
^j Neutrophils decreased (n=79)
^k Pancytopaenia, including fatal events, was not observed in the clinical trial with decitabine/cedazuridine, however it was observed in clinical trials with IV decitabine at a frequency of uncommon (<1%)
^l Differentiation syndrome and interstitial lung disease were not observed in the clinical trial with decitabine/cedazuridine, however they were observed in post-market setting with the use of IV decitabine
^m Hyperglycemia (n=72)
ⁿ Headache and epistaxis Grade 3-4, were not observed in the clinical trial with decitabine/cedazuridine, however they were observed in clinical trials with IV decitabine at a frequency of common (1% and 2%)
° Cardiomyopathy was not observed in the clinical trial with decitabine/cedazuridine, however it was observed in clinical trials with IV decitabine at a frequency of uncommon (<1%)
^p Grouped terms include aphthous ulcer, glossitis, oral discomfort, oropharyngeal discomfort, oropharyngeal pain, stomatitis, tongue ulceration, toothache q Nausea and bilirubin increased, Grade 3-4, were not observed in the clinical trial with decitabine/cedazuridine, however it was
observed in clinical trials with IV decitabine at a frequency of uncommon (<1%)
^r Diarrhoea and vomiting, Grade 3-4, were not observed in the clinical trial with decitabine/cedazuridine, however they were observed in clinical trials with IV decitabine at a frequency of common (2% and 1%)
^s Caecitis (including fatal events) was not observed in the clinical trial with decitabine/cedazuridine, however they were observed in post-market setting with the use of IV decitabine
^t Aspartate aminotransferase increased (n=72) u Alanine aminotransferase increased (n=73)
^v Alkaline phosphatase increased (n=71)
^w Bilirubin increased (n=73)
^x Acute febrile neutrophilic dermatosis was not observed in the clinical trial with decitabine/cedazuridine, however it was observed
in clinical trials with IV decitabine (all Grades) at a frequency of uncommon (<1%)
^y Not applicable (Grade 3-4): Adverse drug reaction has not been observed with either decitabine/cedazuridine or IV decitabine in both clinical trials and post-market
^z Grouped terms include chills and pyrexia
CTCAE = Common Terminology Criteria for Adverse Events

Description of selected adverse reactions

Haematologic adverse drug reactions

The most commonly reported haematologic adverse drug reactions associated with treatment included leukopaenia, thrombocytopaenia, anaemia, neutropaenia and febrile neutropaenia. These adverse drug reactions are manifestations of myelosuppression and may present as pancytopenia.

Serious bleeding-related adverse drug reactions, such as gastrointestinal haemorrhage and cerebral haemorrhage in the context of severe thrombocytopaenia, were reported in patients receiving treatment. Bleeding may also occur with the eyes, skin, and mucous membranes (mouth and anorectal).

Haematological adverse drug reactions must be managed by routine monitoring of CBCs and early administration of supportive treatments as required. Supportive treatments include administration of prophylactic antibiotics and/or growth factor support (e.g., G-CSF) for neutropaenia and transfusions for anaemia or thrombocytopaenia according to institutional guidelines.

Infections and infestations adverse drug reactions

Serious infection-related adverse drug reactions, with potentially fatal outcome, such as septic shock, sepsis, pneumonia, and other infections (viral, bacterial and fungal) were reported in patients receiving treatment.

Gastrointestinal disorders

Occurrences of enterocolitis, including neutropaenic colitis, have been reported during treatment. Enterocolitis may lead to septic complications and may be associated with fatal outcome.

Respiratory, thoracic and mediastinal disorders

Cases of interstitial lung disease (including pulmonary infiltrates, organising pneumonia and pulmonary fibrosis) without signs of infectious aetiology have been reported in patients receiving intravenous decitabine.

Differentiation syndrome

Cases of differentiation syndrome (also known as retinoic acid syndrome) have been reported in patients receiving intravenous decitabine. Differentiation syndrome may be fatal and symptoms and clinical findings include respiratory distress, pulmonary infiltrates, fever, rash, pulmonary oedema, peripheral oedema, rapid weight gain, pleural effusions, pericardial effusions, hypotension and renal dysfunction. Differentiation syndrome may occur with or without concomitant leucocytosis. Capillary leak syndrome and coagulopathy can also occur.

Other special populations

Elderly

Of the 80 patients in clinical studies who received decitabine/cedazuridine, 39% were younger than 75 years, and 61% were 75 years and older. No overall differences in safety or effectiveness were observed between patients aged 75 years and older and younger patients.